Management of Raynaud’s phenomenon in systemic sclerosis—a practical approach

Abstract

Raynaud’s phenomenon is nearly universal in systemic sclerosis. Vasculopathy is part of systemic sclerosis. Raynaud’s phenomenon can cause of complications and impairment, especially when tissue ischemia and digital ulcers develop. There are many treatment options for Raynaud’s phenomenon in systemic sclerosis often with sparse data and few robust studies comparing the different treatment options. Recommendations from guidelines usually include calcium channel blockers as first-line pharmacological treatment. In the clinical setting, multiple variables such as financial factors, geography where access to medications varies, and patient factors, baseline hypotension, can influence the treatment for Raynaud’s phenomenon and digital ulcers. Prostacyclins and PDE-5 inhibitors are reserved for more severe Raynaud’s phenomenon or healing of digital ulcers. Prevention of digital ulcers may also include endothelin receptor blocker (bosentan) in some countries. Other treatments had less consensus. Algorithms developed by systemic sclerosis experts might be helpful in deciding which treatment to choose for each setting, using a step-wise strategy, which intends to complement guidelines. This review focuses on a practical approach to the treatment of Raynaud’s phenomenon and digital ulcers in systemic sclerosis, based on algorithms designed by systemic sclerosis experts using consensus, and we review the evidence that supports treatment from initial to second and third-line options.

Introduction

Raynaud’s phenomenon (RP) is present in the majority of patients diagnosed with systemic sclerosis (SSc). RP in SSc is associated with structural abnormalities of the microvasculature and an immune response. ¹ When RP occurs in the context of a defined condition (SSc), it is called secondary RP, as opposed to primary when it is idiopathic (not associated with an underlying condition). RP is characterized by episodes of vasospasm especially in digital arteries/arterioles. Distal areas of the body are the most affected (fingers, toes, and occasionally nose and ears), more exposed to ambient temperature changes. ² Differences in blood flow are divided into three phases according to the skin color: ischemia (pallor), hypoxia (blue), and reperfusion (red). The main symptoms of RP in SSc are pain, paresthesia and, in case of a persistent alteration of the blood flow, significant tissue ischemia including development of digital ulcers (DUs). ³ DU can appear in half of SSc patients, and at any time, one in six patients has finger ulcers. ⁴ The pathogenesis of vascular alterations is based on endothelial damage, which leads to a dysregulation of cytokines, vasoactive factors, growth factors, cells in the vessels, and inflammatory cells. This causes oxidative stress and hypoxia. Fibroblasts become activated, resulting in an increase in the endothelial collagen matrix deposition, resulting in fibrosis.^2,5 Blood vessels can become fully obliterated.

RP has a severe impact in quality of life of SSc patients.^6,7 Therefore, providing effective treatment including managing complications like DU is necessary. The design of randomized clinical trials (RCTs) in RP and DU is challenging. The definition of DU in clinical trials should be standardized. ⁸ The heterogeneity of the presentations, the variability of RP symptoms according to temperature, and outcome measurements present difficulties. ⁹ For instance, objective measures for RP are difficult to record (as the attacks are episodic) and there is difficulty in determining an active DU versus one that is nearly healed. Only one outcome measure scale (Raynaud’s condition score (RCS)), considering quantitative metrics, disability, pain measures, and psychological effects, has been validated. ⁷ However, trials have used pain, RP frequency, duration, and severity measures, among others. Outcome measurement tools should be developed and validated to improve the assessment of treatment response. ¹⁰ European League Against Rheumatism/EULAR Scleroderma Trials and Research Group (EULAR/EUSTAR) and British Society for Rheumatology (BSR) recommendations provide treatment options for RP and DU, but indications on whether to choose one treatment over another are scarce. ¹¹

The main objective of this article is to review the different treatment strategies with favorable scientific data for RP and DU in SSc, based on the algorithms elaborated by a group of SSc experts in 2017. ¹²

Guidelines for the treatment of SSC-related RP and DU

There are two recent SSc recommendations regarding RP and DU: the 2016 EULAR/EUSTAR ¹³ and the 2016 BSR ¹⁴ guidelines.

RP

The 2016 EULAR/EUSTAR SSc guidelines ¹³ recommend dihydropyridine-type calcium channel blockers (CCBs) (such as nifedipine) as a first-line treatment option, considering the safety profile and the long experience. In severe RP or failing first-line CCB treatment, phosphodiesterase 5 inhibitors (PDE5i) may be considered. Intravenous (IV) iloprost is reserved for severe RP, usually after oral treatments. Fluoxetine might be considered as an alternative treatment for mild RP when side effects limit vasodilator use. The BSR guidelines ¹⁴ recommend CCB and angiotensin II receptor blockers (ARBs) as first-line treatments. Other alternative oral agents such as selective serotonin reuptake inhibitors, α-blockers, and PDE5i are suggested. IV prostanoids and digital sympathectomy should be considered in severe/refractory cases.

DUs

EULAR guidelines suggest the use of IV iloprost or PDE5i inhibitors for DU healing. ¹³ Bosentan, a dual endothelin receptor antagonist (ERA), can be considered for prevention of DUs, IV prostanoids may heal and possibly reduce new DUs, and digital sympathectomy may be considered for severe RP. The BSR guidelines recommend optimizing oral vasodilators (such as CCBs) and to treat pain with analgesics and infection if present with antibiotics. In cases with severe DUs, sildenafil or IV prostanoids are used and bosentan may be considered for the prevention of recurrent DUs. Digital sympathectomy or botulinum toxin may be considered in severe/refractory cases.

Expert consensus treatment algorithms

In 2012, algorithms were developed by SSc experts to assess how and in which order the different treatments in SSc could be tiered for each manifestation including RP and DUs. ¹⁵ In 2018, a Delphi exercise updated the algorithms using international experts from the Scleroderma Clinical Trial Consortium and Canadian Scleroderma Research Group. ¹² The experts were clinicians who saw many SSc patients (86% reported visiting >50 SSc patients per year in their practices). The new algorithms provided a step-wise therapeutic approach, suggesting other treatment when patients failed a previous therapy.

RP algorithm

The algorithm for the treatment of SSc-related RP (Figure 1) reached high agreement among experts (79% vs 66% in 2012). The algorithm included successive treatments according to the severity of RP (<5 attacks per week or >25 as examples of mild and severe RP) and some ancillary treatments (i.e. aspirin, statins) that experts might consider adding to the treatments contained in the main algorithm. Generally, these are potential adjunctive treatments with less supporting literature. There are some medications that are not be approved or available in certain geographical locations such as bosentan for the prevention of DU (approval in Europe and not in North America) and PDE5i which lack approval and thus are not reimbursed in many regions. The suggested doses and most common side effects of the most representative drugs are described in Table 1.

Figure 1.

Algorithm for the treatment of SSc-related Raynaud’s phenomenon.

Modified from Fernández-Codina et al. ¹²

CCB: calcium channel blocker; PDE5i: phosphodiesterase 5 inhibitors; ARB: angiotensin receptor blocker; RP: Raynaud’s phenomenon. Note that in some countries or regions, certain prostanoids may have prescription restrictions or may not be available.

^†Should be applicable to all patients regardless pharmacological therapy. *Only if blood pressure is not low and previous drug was tolerated and gave some benefit.

Table 1.

Pharmacological treatments for systemic sclerosis–related Raynaud’s phenomenon.

Drug	Dose	Common side effects
CCBa,b
Nifedipine	10–30 mg TID PO	Hypotension, headache, peripheral edema, flushing, dizziness, tachycardia
Nifedipine XL	30–60 mg OD or BID PO
Amlodipine	5–10 mg OD PO
Felodipine	2.5–10 mg BID PO
PDE-5 inhibitorsa,b
Sildenafil	20–25 mg TID or 50 mg BID PO	Hypotension, headache, flushing, epistaxis, dyspepsia
Tadalafil	20 mg OD alternate days or 20 mg OD to BID PO
Vardenafil	10 mg BID PO
ARB a
Losartan	25–50 mg OD PO	Hypotension, dizziness, weakness, fatigue, diarrhea, cough
Prostanoidsa,b
Iloprost	0.5–2 ng/kg/min IV for 6–24 h during 2–5 days monthly	Hypotension, flushing, cough, nausea, headache, trismus, palpitations, arrhythmia, acute pulmonary edema
Alprostadil	20 µg/h IV for 3 h during 5 days monthly
Epoprostenol	2 ng/kg/min IV continuous
ERA b
Bosentan	62.5–125 mg BID PO	Hypotension, flushing, edema, headache, liver enzyme elevation
Ancillary treatments
Aspirin a	81 mg OD PO	Allergy, bleeding, gastroesophageal reflux
Atorvastatina,b	40 mg OD PO	Diarrhea, myalgia
Fluoxetine a	20 mg OD PO	Headache, nausea, anorexia, dry mouth
Pentoxifylline a	400 mg TID PO	Nausea, vomiting
Topical nitrates (nitroglycerin) a	0.9%–2% ointment up to 4 times daily in the web spaces (proximal finger) of the affected fingers	Headache

CCBs: calcium channel blockers; XL: extended release; PDE5i: phosphodiesterase 5 inhibitors; ARB: angiotensin receptor blocker; PO: oral; IV: intravenous; OD: once daily; BID: twice daily; TID: three times daily.

^aPositive data for Raynaud’s phenomenon treatment.

^bPositive data for digital ulcer treatment.

Non-pharmacological measures

Non-pharmacological measures should be implemented in all patients as first-line therapy. Avoiding damaging the microvasculature (such as exposure to extreme cold, smoking, and vibration injury) is advisable but high-level evidence is lacking for environmental exposure cessation/avoidance. Some drugs like sympathomimetics, ergot alkaloids, and bleomycin have been associated with RP. It is controversial whether beta-blockers exacerbate RP. ¹⁶

CCBs

Dihydropyridine CCBs (especially nifedipine) are first-line drug treatment in RP. A meta-analysis of CCB treatment for primary and secondary RP was published in 2017 which showed positive results. ¹⁷ A total of 34 double-blinded RCTs and 4 single-blinded RCTs were included. Only four studies compared a non-dihydropyridine CCB (three diltiazem and one verapamil) to placebo, obtaining less impressive results than the pooled dihydropyridine trials. CCB outcomes in patients with secondary RP evaluated the frequency of RP attacks (attacks/week) and severity (average, on a 10-cm visual analogue scale (VAS)). For all patients with secondary RP, frequency of the attacks diminished by a mean difference of −3.15 attacks (95% confidence interval (CI) −3.67, −2.63) (nine studies, including 204 participants) and severity dropped by a mean difference of −0.48 (95% CI −0.61, −0.35) (six studies, including 138 participants). In a subanalysis of secondary RP patients treated with nifedipine versus placebo, frequency of the attacks diminished by a mean difference of −4.19 (95% CI −5.47, −2.91) (six studies, including 120 participants) and severity of the attacks reduced by a mean difference of 0.01 (95% CI −0.32, 0.34) (three studies, including 54 participants). CCBs were effective in reducing the frequency of the episodes and the intensity of the attacks, but effects were attenuated in secondary RP (mostly patients with SSc were studied) versus primary RP. This was probably influenced by the presence of established vascular disease (vasculopathy) in SSc.

PDE5i

PDE5i were second-line choice for mild RP and second or third choice (in combination with prostanoids) for severe RP. Their mechanism of action is based on increasing the availability of nitric oxide. A meta-analysis performed in 2013 included three drugs (sildenafil, tadalafil, vardenafil), six double-blinded RCT studies, and 244 patients mostly with SSc-related RP (92%). ¹⁸ The meta-analysis found that PDE5i significantly decreased RCS by −0.46 (95% CI −0.74, 0.17), frequency of the attacks by −0.49 (95% CI −0.71, −0.28), and daily duration of RP attacks by −14.62 min (−20.25, −9). Overall, PDE5i seemed moderately effective to treat SSc-related RP. Recently, a randomized, double-blind, N-of-one trial in primary and secondary RP patients compared on-demand treatment (before exposure to triggers or at the beginning of an attack) using placebo versus sildenafil in two different doses (40 and 80 mg). ¹⁹ The study showed that on-demand sildenafil was not superior; with high heterogeneity and a small effect size, but stated that the likelihood of sildenafil being more effective than placebo was 90%. A double-blinded RCT comparing udenafil versus amlodipine showed no differences in the treatment of secondary RP. ²⁰ No other oral PDE5i versus CCBs have been published. Currently, generic sildenafil is available, which may reduce costs. However, due to lack of approval of PDE5i for this indication, access for patients may be limited. Thus, CCBs are recommended as the first-line drug treatment in RP due to experience with CCB and lack of superiority of PDE5i in one trial over CCB and access issues with PDE5i.

Angiotensin II receptor type 1 blockers

Reserved as a third-line treatment for mild RP, only one unblinded RCT including 52 patients with either primary or SSc-related RP studied nifedipine (20 mg BID) and losartan 50 mg daily. ²¹ In patients with SSc, the severity of RP episodes decreased by 36% in the losartan group and 9% in the nifedipine group. The frequency of the RP episodes decreased by 45% with losartan and increased by 56% with nifedipine. It is unknown whether higher doses of either medication could have been more effective. Losartan is widely available, accessible, and has an acceptable side effect profile. It is often reserved for nifedipine failures, and in this population, it has not been studied and clinically it is our opinion that the effectiveness in this group of patients is low.

Prostanoids

Generally recommended by the experts as a rescue therapy for refractory severe RP, prostanoids induce vasodilation activating the prostacyclin receptors. One meta-analysis pooled seven RCTs with 332 patients, analyzing the subset with SSc-related RP. ²² There was one study each with oral iloprost, another with oral cicaprost, and the rest had IV iloprost. The frequency of attacks had a trend toward favoring iloprost with a Weighted Mean Difference (WMD) of −0.8 (95% CI −4.71, 3.11), whereas analyzing the IV iloprost studies, only one resulted in statistical significance. Oral prostacyclin analogues (iloprost, ²³ cicaprost, ²⁴ beraprost ²⁵ ) and an oral prostacyclin receptor analogue (selexipag ²⁶ ) have failed to show benefits for secondary RP. Infusion of IV iloprost has different protocols. There is no study comparing the different schemes. Ingegnoli et al. ²⁷ conducted a Delphi exercise to address this question. Experts agreed that for severe SSc-related RP, IV iloprost should be infused for 1–3 days monthly, infusing 0.5–2 ng/kg/min (suggesting titrating doses based on tolerability) for 6 h per day. The use of central lines versus peripheral lines was not discussed. However, the standard protocol in trials was frequently daily treatment for five consecutive days using peripheral IV access. Iloprost has many side effects and it is not universally available (such as no current access in the United States). Costs are increased due to need for daily IV treatment over a period of time. Some other prostanoids have some weaker evidence for secondary RP treatment. IV alprostadil has conflicting results versus placebo in two trials: one showing a beneficial effect ²⁸ and another showing no benefit after the infusion was stopped. ²⁹ In a small direct comparison with IV iloprost, alprostadil was effective for Connective Tissue Disease (CTD)-related RP at a lower cost. ³⁰ Epoprostenol, another prostacyclin analogue, is approved to treat pulmonary arterial hypertension (PAH). A systematic review ³¹ only found one PAH RCT (epoprostenol plus standard of care vs standard of care alone) ³² that showed a trend toward an improvement of a RP VAS, and significantly lower area under the curve for severity of RP over time, favoring epoprostenol.

Other pharmacological options

Some treatments were removed from the algorithms suggested by experts but were regarded as ancillary treatments (these treatments have in common a limited amount of evidence supporting them (uncontrolled, observational studies)), an acceptable safety profile, low cost, and the possibility of combining them with the treatments already included in the algorithms, without significant potential interactions. Platelet activation is a well-documented phenomenon in RP and tackling this mechanism might be a logical step. Only one positive clinical trial has explored this possibility. ³³ Atorvastatin was tried for a short period in SSc patients with RP and DU, reducing the RP VAS. ³⁴ A small randomized crossover study with primary and secondary RP patients compared fluoxetine 20 mg to nifedipine 40 mg daily. Fluoxetine showed no effect on blood pressure but a statistically significant decrease in the RP attack severity and frequency from onset to end of trial. ³⁵ A recent subanalysis of the RISE-SSc RCT comparing riociguat to placebo in patients with early diffuse SSc failed to show improvement in RP. ³⁶ Finally, topical nitrates use was evaluated by a meta-analysis ³⁷ including seven placebo-controlled trials, which summarized the different outcome measures in a single RP treatment effect size scale. The subgroup analysis for secondary RP showed a benefit which was statistically significant favoring topical nitrates.

Procedures

Minimally invasive or surgical procedures were regarded as the fifth line for treatment of severe RP. Evidence regarding subcutaneous injection of botulinum toxin is based in two RCTs. In 2017, Motegui et al. ³⁸ conducted a single-blinded trial in SSc patients with a no treatment control group, showing a statistically significant decrease in RCS and the RP pain VAS over time in all the doses tested (250, 1000, and 2000 U of botulinum toxin A distributed through the interdigital web spaces). Conversely, a 40-SSc-patient double-blind placebo-controlled (one hand was injected in the same web spaces 50 U of botulinum toxin A, while the others got saline placebo injections) RCT in 2018 ³⁹ did not show significant changes in the RCS or in the RP pain VAS. Hence, the use of botulinum toxin A is still controversial. Surgical digital sympathectomy lacks RCTs and has been used historically in refractory patients. Different techniques have been reported and a systematic review by Herrick shows heterogeneous results that cannot be interpreted. ⁴⁰ Again, its use shall be individualized according to each case and only for patients with refractory RP.

DU algorithm

The algorithm created using expert opinion for the treatment of DU in SSc is shown in Figure 2. This algorithm improved the previous overall agreement from 58% to 66%. It is divided into two differentiated arms: DU prevention and DU treatment. Treatment details are shown in Table 1.

Figure 2.

Algorithm for the treatment of SSc-related DUs.

Modified from Fernández-Codina et al. ¹²

CCB: calcium channel blockers; PDE5i: phosphodiesterase 5 inhibitors. Note that in some countries or regions, certain drugs (i.e. prostanoids, bosentan) may have prescription restrictions or may not be available.

^†Should be applicable to all patients regardless pharmacological therapy. *Only if blood pressure is not low and previous drug was tolerated and gave some benefit.

Non-pharmacological measures

Avoiding RP attacks, keeping warm and reducing fingertip trauma may reduce DU occurrence or worsening.

Ruling out other causes of DUs and wound care

When a DU occurs in SSc, an assessment should be considered to rule out other mimicking conditions and complications that would have other specific treatments (i.e. thrombus, macrovascular disease, severe infection, etc). Control of the pain is needed. ⁴¹ The management of the wounds is complex, and for large ulcers, involvement of experienced wound care personnel, surgeons, or infectious diseases specialists could be beneficial. Wound care strategies, like the TIME concept (Tissue, Infection, Moisture, Edge), ⁴² may be used, although no specific schemes exist for SSc DUs. Eschar debridement may be necessary. The risk of infection in severe DUs was as high as two in three patients in one case series. ⁴³ Dressings can include silver nitrate or iodine to decrease local infection. Empirical systemic antibiotic treatment should be prescribed according to the local common microbiologic isolates and resistance patterns when infection is severe. Therefore, maintaining protection of the ulcer with dressings and topical treatment may be helpful.

CCBs

Only one RCT has assessed the effect of CCB in SSc-DU. Rademaker et al. ⁴⁴ conducted a very small study (23 patients), comparing IV iloprost versus oral nifedipine (30–60 mg daily). Both treatments effectively reduced the number of skin lesions (DU), but IV iloprost was significantly superior. CCBs are inexpensive often with mild side effects so it is often considered as first-line treatment in DUs in SSc.

PDE5i

Evidence for the use of PDE5i in the treatment of active DUs in SSc was confirmed in a meta-analysis. ⁴⁵ Three studies (two sildenafil, one tadalafil) including 85 participants showed a statistically significant beneficial effect for the healing of DU (risk ratio (RR) 3.28 (95% CI 1.32, 9.13)) and the number of patients with DU improvement (RR 4.29 (95% CI 1.73, 10.66)). Moreover, a placebo-controlled RCT in 2016, the SEDUCE study, ⁴⁶ failed to demonstrate differences between sildenafil and placebo in the time to heal each DU (likely due to an unexpected high DU healing rate in the placebo group or due to the timing of the end point as eventually most ulcers heal, so if wait time is too long, differences will diminish between a treatment and placebo). A significantly lower mean number of DUs in the sildenafil group at 8 and 12 weeks was found as well as a greater healing rate. Regarding the prevention of new DUs, only tadalafil had positive data. In a single crossover RCT, only one new DU was reported during tadalafil treatment in SSc as compared with 13 during placebo treatment. PDE5i is costly relative to CCBs and access is not universal as all treatments of RP and DU are off-label.

Bosentan

Bosentan is the only dual ERA approved for the prevention of DU in SSc. The RAPIDS 1 and 2 studies were the two RCTs contained in a meta-analysis (310 patients, bosentan vs placebo for DUs). ⁴⁵ The number of new DUs per patient was not very different if there were no baseline DU, but if there were multiple ulcers, then the prevention effect was better comparing bosentan to placebo. ⁴⁷ In contrast, there is no healing effect for bosentan. Bosentan is the only approved for DU prevention and it is not approved at all for this indication in North America. Macitentan, a more recent dual selective ERA, failed to reduce new DUs among patients with SSc. ⁴⁸

Prostanoids

Prostanoids were, for most experts, the rescue treatment for refractory patients or in cases of critical ischemia and DU in the context of SSc-RP. ¹² As mentioned, IV iloprost vas superior to oral nifedipine reducing the number of DUs in SSc. ⁴⁴ A meta-analysis of four RCTs with oral and IV prostacyclin analogues showed a trend for prostanoids in healing DU (RR 1.33 (95% CI 0.97, 1.84)). ⁴⁵ Regarding the prevention of new DUs, the pooled data for all prostacyclin studies were negative. IV iloprost showed some benefit preventing new DUs (RR −0.77 (95% CI −1.46, −0.08)). ⁴⁹ Recently, a new RCT with oral treprostinil failed to reduce the DU burden compared to placebo. ⁵⁰

Digital sympathectomy

There are no RCTs that support digital sympathectomies. Digital sympathectomy could improve pain management and prompt DU healing, although the recurrence rate in SSc may occur in one-third of patients. ⁵¹ Experts would only perform it occasionally in refractory and critical cases. ¹²

Other treatments

In a single-site placebo-controlled trial, ³⁴ atorvastatin statistically significantly reduced DU pain and DU severity. The development of new DUs was also decreased in the atorvastatin group. One single-blind RCT showed an improvement in the healing of DU and a reduction in the appearance of new DU in SSc patients treated with B botulinum toxin injections in the fingers’ webs (1000–2000 U). ³⁸ The RISE-SSc study comparing riociguat to placebo in early diffuse SSc patients did not show a statistically significant reduction in DU recurrence. ³⁴

Future perspectives

The development and incorporation of therapeutic algorithms to the guidelines endorsed by the scientific societies could facilitate treatment based on expert opinion when trials are lacking. The research agenda could include development of outcome measurement scales in RP and DU taking into account patients’ avoidance of triggers and impact of RP and DU in quality of life. Head-to-head trials, trials to define effective doses, or other innovative trial designs may lead to better management of RP and DU in SSc.

Ongoing or enrolled RP trials in RP at Clinicaltrials.gov include the following: oral treprostinil (NCT02583789), beetroot juice (NCT03129178), tadalafil–Delivra cream (NCT03393325), abobotulinum Toxin A (NCT03639766), diosmiplex (NCT02683408), and PF-00489791 (NCT01090492), a phosphodiesterase inhibitor. Two specific trials in SSc-associated RP are registered: electrotherapy with galvanic current (NCT03699436) and α2C-adrenoceptor antagonist ORM-12741 (NCT01315899).

Regarding SSc DUs, the following studies are active or have completed their recruitment: iontophoresis of treprostinil (NCT03120533), topical ambrisentan (NCT00725361), ozone therapy (NCT02733978), autologous fat grafting (NCT03406988), riociguat (NCT02915835), and botulinum toxin type B (NCT03007004).

Conclusion

RP occurs in nearly all patients with SSc and half will have DU. These complications influence the quality of life of patients. The evidence available has limitations and choosing the adequate treatment for each clinical situation might be challenging. Expert-designed algorithms can help making therapeutic decisions, adopting a step-wise approach, according to the literature and clinical experience. For both RP and DUs, non-pharmacological measures and/or CCB (especially nifedipine) are initially used. PDE5i, bosentan, and other treatments vary in their use depending on access and prescribing preferences. For RP CCB, ARB, PDE5i, and prostanoids are the main pharmacological options. For DU treatment and prevention, CCB, PDE5i, and prostanoids are used, and in some countries, bosentan is used for the prevention of multiple DU. Other treatments can be useful, according to the patients’ characteristics and condition (such as nitrates, α-blockers, selective serotonin reuptake inhibitors, botox, sympathetic blocks, and biofeedback). There is a need for improved trial design in order to continue to explore therapies as there is still unmet need in SSc for RP and DU.